Purpose

To determine the maximum tolerated dose (MTD) of [¹³¹I]tositumomab in patients with refractory/recurrent Hodgkin lymphoma (HL) and to preliminarily determine if [¹³¹I]tositumomab has activity against HL and if positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]DG) performed 6 weeks post-therapy predicted 12-week response.

Procedures

Separate dose-finding studies were performed for patients with and without prior transplant. A single therapeutic total body radiation dose (TBD) of [¹³¹I]tositumomab was administered. TBD was escalated/de-escalated based on dose-limiting hematologic toxicity (DLT) using a modified continual reassessment method. [¹⁸F]DG-PET/CT scans were performed at baseline and 6 and 12 weeks post therapy.

Results

Twelve patients (nine classical HL, three lymphocyte-predominant [LP] HL) completed two dosing levels (n = 3 each) in the post-transplant (55 cGy, 79 cGy) and no transplant (75 cGy, 87 cGy) groups. Hematologic toxicities were common and transient. Twelve weeks after [¹³¹I]tositumomab, 10 patients progressed and two with LPHL achieved complete response. [¹⁸F]DG-PET/CT at 6 weeks post therapy appeared more predictive than CT at 6 weeks of a response at 12 weeks.

Conclusions

Tositumomab and [¹³¹I]tositumomab was well-tolerated in patients with relapsed/refractory HL. Complete responses in LPHL support a therapeutic effect in this subtype. Early metabolic response assessments by [¹⁸F]DG-PET in HL after radioimmunotherapy appear to be more predictive than purely anatomic assessments.

Purpose

The aims of this study were to determine whether pretreatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine whether pretreatment levels of these molecules were associated with response to treatment and/or survival.

Experimental design

We quantified plasma levels of B-cell activation-associated molecules (sCD27, sCD30, and sCD23) and cytokines (IL6, IL10, and CXCL13) before and after the initiation of treatment in persons with AIDS-NHL (n = 69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab.

Results

Treatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, and sCD30), with decreased levels persisting for one year following the completion of treatment. Lower levels of CXCL13 before treatment were associated with complete responses following lymphoma therapy. Elevated levels of IL6 pretreatment were associated with decreased overall survival, whereas higher IL10 levels were associated with shorter progression-free survival (PFS), in multivariate analyses. Furthermore, patients with CXCL13 or IL6 levels higher than the median levels for the NHL group, as well as those who had detectable IL10, had lower overall survival and PFS, in Kaplan-Meier analyses.

Conclusions

These results indicate that CXCL13, IL6, and IL10 have significant potential as prognostic biomarkers for AIDS-NHL.

Emerging evidence shows that tumor cells secrete extracellular vesicles (EVs) that carry bioactive cell surface markers, such as programmed death-ligand 1 (PD-L1), which can modulate immune responses and inhibit anti-tumor responses, potentially playing a role in lymphomagenesis and in promoting the growth of these cancers. In this study, we investigated the role of EVs expressing cell surface molecules associated with B cell activation and immune regulation. We measured levels of EVs derived from plasma from 57 subjects with AIDS-related non-Hodgkin lymphoma (AIDS-NHL) enrolled in the AIDS Malignancies Consortium (AMC) 034 clinical trial at baseline and post-treatment with rituximab plus concurrent infusional EPOCH chemotherapy. We found that plasma levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII were significantly reduced after cancer treatment. AIDS-NHL patients with the diffuse large B cell lymphoma (DLBCL) tumor subtype had decreased plasma levels of EVs bearing PD-L1, compared to those with Burkitt's lymphoma. CD40, CD40L and TNF-RII-expressing EVs showed a significant positive correlation with plasma levels of IL-10, CXCL13, sCD25, sTNF-RII and IL-18. Our results suggest that patients with AIDS-NHL have higher levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII in circulation before cancer treatment and that levels of these EVs are associated with levels of biomarkers of microbial translocation and inflammation.

Purpose

The aims of this study were to determine whether pretreatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine whether pretreatment levels of these molecules were associated with response to treatment and/or survival.

Experimental design

We quantified plasma levels of B-cell activation-associated molecules (sCD27, sCD30, and sCD23) and cytokines (IL6, IL10, and CXCL13) before and after the initiation of treatment in persons with AIDS-NHL (n = 69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab.

Results

Treatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, and sCD30), with decreased levels persisting for one year following the completion of treatment. Lower levels of CXCL13 before treatment were associated with complete responses following lymphoma therapy. Elevated levels of IL6 pretreatment were associated with decreased overall survival, whereas higher IL10 levels were associated with shorter progression-free survival (PFS), in multivariate analyses. Furthermore, patients with CXCL13 or IL6 levels higher than the median levels for the NHL group, as well as those who had detectable IL10, had lower overall survival and PFS, in Kaplan-Meier analyses.

Conclusions

These results indicate that CXCL13, IL6, and IL10 have significant potential as prognostic biomarkers for AIDS-NHL.

Purpose

AIDS-related non-Hodgkin lymphoma (ARL) is the most common cancer in HIV-infected individuals in the United States and other countries in which HIV-positive persons have access to effective combination antiretroviral therapy (cART). Our prior work showed that pretreatment/postdiagnosis plasma levels of some cytokines, such as IL6, IL10, and CXCL13, have the potential to serve as indicators of clinical response to treatment and survival in ARL. The aims of this study were to identify novel prognostic biomarkers for response to treatment and/or survival in persons with ARL, including biomarkers of microbial translocation and inflammation.

Experimental design

We quantified plasma levels of several biomarkers (sCD14, LBP, FABP2, EndoCab IgM, IL18, CCL2/MCP-1, sCD163, IP-10/CXCL10, TARC/CCL17, TNFα, BAFF/BLyS, sTNFRII, sCD44, and sIL2Rα/sCD25) by multiplexed immunometric assays (Luminex) or ELISA in plasma specimens obtained from ARL patients enrolled in the AMC-034 trial, which compared infusional combination chemotherapy (EPOCH: etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) with concurrent or sequential rituximab. Plasma was collected prior to the initiation of therapy (n = 57) and after treatment initiation (n = 55).

Results

We found that several biomarkers decreased significantly after treatment, including TNFα, sCD25, LBP, and TARC (CCL17). Moreover, pretreatment plasma levels of BAFF, sCD14, sTNFRII, and CCL2/MCP-1 were univariately associated with overall survival, and pretreatment levels of BAFF, sTNFRII, and CCL2/MCP-1 were also associated with progression-free survival.

Conclusions

Our results suggest that patients with ARL who responded to therapy had lower pretreatment levels of inflammation and microbial translocation as compared with those who did not respond optimally.

The objective of this study was to explore the cancer incidence rates among HIV-infected persons with commercial insurance who were on antiretroviral therapy and compare them with those rates in the general population. Paid health insurance claims for 63,221 individuals 18 years or older, with at least one claim with a diagnostic code for HIV and at least one filled prescription for an antiretroviral medication between January 1, 2006, and September 30, 2012, were obtained from the LifeLink® Health Plan Claims Database. The expected number of cancer cases in the general population for each gender-age group (<30, 30-39, 40-49, 50-59, and >60 years) was estimated using incidence rates from the Surveillance Epidemiology and End Results (SEER) program. Standardized incidence ratios (SIRs) were estimated using their 95% confidence intervals (CIs). Compared to the general population, incidence rates for HIV-infected adults were elevated (SIR, 95% CI) for Kaposi sarcoma (46.08; 38.74-48.94), non-Hodgkin lymphoma (4.22; 3.63-4.45), Hodgkin lymphoma (9.83; 7.45-10.84), and anal cancer (30.54; 25.62-32.46) and lower for colorectal cancer (0.69; 0.52-0.76), lung cancer (0.70; 0.54, 0.77), and prostate cancer (0.54; 0.45-0.58). Commercially insured, treated HIV-infected adults had elevated rates for infection-related cancers, but not for common non-AIDS defining cancers.

Background and objectives

People living with HIV/AIDS are at an increased risk of developing cancer. The goals of this study were to obtain data on the prevalence of HIV in the cancer population and vice versa at a major tertiary cancer and HIV center in North India.

Methods

This cross-sectional study was conducted over a 3-year period from July 2013 to June 2016, wherein successive HIV positive patients from an anti-retroviral therapy (ART) center were screened for malignancy. Simultaneously, successive cancer patients at the cancer center were screened for HIV. Baseline demographic details, risk factors, and laboratory investigations were obtained for all the patients.

Results

Among the 999 HIV-positive patients at the ART center, the prevalence of malignancy was 2% (n=20; 95% confidence interval (CI) 1.13, 2.87). Among the 998 patients with a malignancy, the prevalence of HIV infection was 0.9% (n=9; 95% CI 0.31, 1.49). Weight loss, loss of appetite, and fever were the most common symptoms in patients with HIV and cancer. Among 29 patients with HIV and cancer, AIDS-defining cancer was found in 19 patients; non-Hodgkin's lymphoma was the most common malignancy reported (n=13).

Interpretation and conclusion

There is a low prevalence of HIV in cancer patients as well as a low prevalence of cancer in HIV patients. AIDS-defining cancers remain much more common than non-AIDS-defining cancers. With the increased coverage of ART, it is expected that non-AIDSdefining cancers will increase, as is evident from data from more developed countries.

Objectives

People with HIV (PWH) are at increased risk for premature cardiovascular disease (CVD). Clonal hematopoiesis is a common age-related condition that may be associated with increased CVD risk. The goal of this study was to determine the prevalence of clonal hematopoiesis and its association with chronic inflammation and CVD in PWH.

Design

Cross-sectional study utilizing archived specimens and data from 118 men (86 PWH and 32 HIV-uninfected) from the Baltimore-Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary computed tomography angiography (CTA) and measurement of 34 serologic inflammatory biomarkers.

Methods

Clonal hematopoiesis was assessed on peripheral blood mononuclear cells utilizing targeted error-corrected next generation sequencing (NGS) focused on 92 genes frequently mutated in hematologic malignancies. Clinical and laboratory data were obtained from the MACS database.

Results

Clonal hematopoiesis with a variant allele frequency (VAF) greater than 1% was significantly more common in PWH [20/86 (23.3%)] than in HIV-uninfected men [2/32 (6.3%)] ( P  = 0.035). PWH with clonal hematopoiesis (VAF > 1%) were more likely to have coronary artery stenosis of at least 50% than those without clonal hematopoiesis [6/20 (30%) vs. 6/64 (9%); P  = 0.021]. Presence of clonal hematopoiesis was not significantly associated with serological inflammatory markers, except for significantly lower serum leptin levels; this was not significant after adjustment for abdominal or thigh subcutaneous fat area.

Conclusion

Clonal hematopoiesis was more common in PWH and among PWH was associated with the extent of coronary artery disease. Larger studies are needed to further examine the biological and clinical consequences of clonal hematopoiesis in PWH.

Background

Clonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited.

Methods

We addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications-a "validation" mode to derive a clonality classifier, and a "live" mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples.

Results

The optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%-90%, specificities of 97%-100%, areas under the curve of 91%-94%, positive predictive values of 92-100%, and negative predictive values of 88%-98%. Customization of the algorithms yielded 95%-100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%-96%.

Conclusions

CR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies.